There is a profound need for therapeutics that prevents nerve cell death in diseases of the nervous system. Examples include Alzheimer's and Parkinson's diseases as well as less frequent conditions such as ALS and Huntington's disease. In addition, there are equally intractable conditions such as stroke and non-AD memory loss. Five years ago a novel small organic pharmacophore was discovered in our laboratory that prevents cell death in a variety of nerve cell death tissue culture paradigms, including amyloid toxicity, neurotrophic factor withdrawal, excitotoxicity, glucose starvation, and oxidative stress. The effect of this compound appears to be nerve specific, for it does not block the apoptotic death of fibroblasts caused by TNF-alpha or staurosporine. The goals of this project are to use combinatorial and medicinal chemistry to improve the efficacy of this neuroprotective compound and then to test these improved versions of the compound in animal models of several age-associated neurological diseases, including AD, Huntington's and ALS. In addition, since the compound keeps CREB levels elevated under conditions of stress, its effectiveness in a mouse memory model will be studied. The results from these studies will determine the therapeutic potential of this novel compound. [unreadable] [unreadable]